A Simple Cellular Model for Lipodystrophy

脂肪营养不良的简单细胞模型

• 批准号: 8069882
• 负责人: JOEL M GOODMAN
• 金额: $ 30.78万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069882
• 关键词: 3T3-L1 Cells; Acyl Coenzyme A; Adipocytes; Adipose tissue; Affect; BSCL2 gene; Binding Proteins; Biological Assay; Cell model; Cells; Co-Immunoprecipitations; Communication; Complex; Cytolysis; Cytoplasm; Defect; Diabetes Mellitus; Diffuse; Disease; Dyslipidemias; Electron Microscopy; Endoplasmic Reticulum; Endosomes; Energy Intake; Enzymes; Familial generalized lipodystrophy; Fatty Liver; Fatty acid glycerol esters; Gene Deletion; Genes; Genomics; Golgi Apparatus; Health; Heart Diseases; Human; Insulin Resistance; Life; Lipase; Lipids; Lipodystrophy; Liver; Maintenance; Membrane; Metabolic Diseases; Monitor; Mus; Muscle; Mutate; Mutation; Nonesterified Fatty Acids; Obesity; Organ failure; Organelles; Pathway interactions; Process; Proliferating; Proteins; Resolution; Risk; Risk Factors; Role; Site; Stroke; Surface; Syndrome; Testing; Tissues; Triglycerides; Vacuole; Vesicle; Work; Yeasts; cellular imaging; design; falls; fatty acid oxidation; gene function; human disease; lipid transport; lipine; luminal membrane; novel; peroxisome; promoter; public health relevance; research study; retrograde transport; stem; trafficking; vacuolar H+-ATPase

DESCRIPTION (provided by applicant): The increased risk of developing heart disease, strokes, and diabetes with excess adipose tissue is well known; obesity is generally caused by excess caloric intake. Less well appreciated are the devastating effects on health of the lipodystrophies. In the most severe forms, adipose tissue is virtually nonexistent, fat is abnormally stored in the liver and muscle, and there is a huge increase in circulating levels of triglycerides and free fatty acids. Metabolic diseases including diabetes, and frank organ failure, often are the results. Neutral fat is normally stored in lipid bodies, which are most apparent in adipocytes, yet the origin of these organelles is mysterious and no known factors that catalyze their assembly have been identified. We propose that defects in assembly and/or maintenance of lipid bodies are a cause of lipodystrophy. A yeast genomic screen for aberrant lipid bodies (observation of gene deletion strains) has revealed 62 genes involved in lipid body assembly or maintenance, three of which are known to cause lipodystrophy in humans or mice. We will study the function of the genes involved in lipodystrophy, particularly seipin, mutations in which cause severe human disease. We will determine if seipin is found at lipid body exit sites of the endoplasmic reticulum and whether it might organize these sites. We will study the murine lipodystrophy gene lipin and its activators, and determine if they are involved in packaging of lipid and protein for lipid bodies. Our screen also detected 17 genes involved in organelle trafficking, especially involving endosomes. We will study three groups of these as they relate to possible roles in retrograde transport of factors involved in lipid body assembly, or possible endosomal communication required for maintenance of lipid bodies. In summary, novel factors for lipid bodies have been identified by our screen and we shall study several of them, especially seipin, to begin to elucidate the steps of lipid body assembly and maintenance. This information should be useful in the lipodystrophies and obesity, and it may prove valuable in the design of novel forms of therapy for these devastating diseases. PUBLIC HEALTH RELEVANCE: Both an absence of fat tissue and an overabundance of fat tissue are major risk factors for heart disease, strokes, diabetes, and organ failure. Fat is stored in cell organelles called lipid bodies, yet how they are formed is a mystery, and what goes wrong in lipodystrophy (absence of fat tissue) is often not clear. Experiments are proposed to understand how lipid bodies are formed and what goes wrong in two types of lipodystrophy.

描述(由申请人提供)：众所周知，脂肪组织过多会增加患心脏病、中风和糖尿病的风险；肥胖通常是由过多的卡路里摄入引起的。较少被认识到的是脂肪营养不良症对健康的破坏性影响。在最严重的情况下，脂肪组织几乎不存在，脂肪异常储存在肝脏和肌肉中，循环中的甘油三酯和游离脂肪酸水平大幅增加。结果往往是包括糖尿病和坦率的器官衰竭在内的代谢性疾病。中性脂肪通常储存在脂体中，这在脂肪细胞中最为明显，但这些细胞器的起源是个谜，目前还没有确定催化它们组装的已知因素。我们认为脂体的组装和/或维护缺陷是导致脂营养不良的原因之一。酵母基因组对异常脂体的筛选(观察基因缺失菌株)发现了62个与脂体组装或维持有关的基因，其中三个已知会导致人类或小鼠的脂肪营养不良。我们将研究与脂肪营养不良有关的基因的功能，特别是seipin，在这些基因突变中，会导致严重的人类疾病。我们将确定是否在内质网的脂体出口部位发现Seipin，以及它是否可能组织这些部位。我们将研究小鼠脂营养不良基因Lipin及其激活物，并确定它们是否参与脂类和脂体蛋白质的包装。我们的筛查还检测到了17个与细胞器运输有关的基因，特别是涉及内体。我们将研究其中的三组，因为它们可能与脂体组装所涉及的因子的逆行运输有关，或者可能与维持脂体所需的内体通讯有关。综上所述，我们的筛选已经确定了脂体的新因素，我们将研究其中的几个因素，特别是Seipin，以开始阐明脂体组装和维持的步骤。这些信息应该对脂肪营养不良和肥胖症有用，它可能被证明在设计针对这些毁灭性疾病的新形式的治疗方面有价值。 公共卫生相关性：脂肪组织缺乏和脂肪组织过多都是心脏病、中风、糖尿病和器官衰竭的主要风险因素。脂肪储存在称为脂体的细胞器中，但它们是如何形成的是一个谜，脂肪营养不良症(没有脂肪组织)的问题通常不清楚。建议进行实验以了解脂体是如何形成的，以及在两种类型的脂肪营养不良中出现了什么问题。